Although postmenopause is a universal experience of aging and is defined by permanent changes in ovarian function, we still do not understand how postmenopausal sex hormones affect diabetes risk. Intriguing observations suggest that endogenous sex hormones (ESH) may contribute to glucose intolerance in postmenopausal women. Previous observational studies have been limited by single measures of ESH, and intervention studies are limited by examination of exogenous hormone only, lack of significant glucose changes, lack of measurement of potential confounders such as insulin homeostasis, or examination only in Caucasians of European ancestry. The Diabetes Prevention Program (DPP) was a large randomized controlled trial (n=3,234) of intensive lifestyle intervention and metformin for prevention of diabetes. The DPP enrolled participants with either impaired fasting glucose or impaired glucose tolerance, 45% of whom were non-white, and the DPP also obtained multiple measures of anthropometry, insulin secretion, insulin sensitivity, and fasting and postchallenge glucose. Approximately two-thirds were women, and half of the women were postmenopausal at baseline. Thus, the DPP offers a compelling opportunity to examine the contribution of changes in endogenous sex hormones (ESH) to the evolution of glucose intolerance in postmenopausal women. We propose an ancillary study to the DPP, the Sex Hormones in Postmenopausal Women or SHIP study. Using plasma stored from the baseline data collection and 2 years after randomization, we propose to examine ESH (testosterone, estradiol, sex hormone binding globulin) and follicle stimulating hormone (FSH) in a subset of DPP women without exogenous hormone use (n=865) and DPP women with exogenous hormone use (n=144) using state-of-the art mass spectrometry. Specific Aim 1 is to examine if diabetes prevention interventions are associated with changes in ESH. Specific Aim 2 is to examine if changes in ESH levels are associated with changes in glucose by intervention arm. Specific Aim 3 is to examine whether changes in adiposity, insulin sensitivity, and insulin secretion explain these associations. Investigators and consultants on this proposal are involved in the Study of Women's Health Across the Nation expert in ESH life stage transitions, as well as DPP PIs who have conducted the initial research in ESH that form the basis for this study. The team includes sex hormone biologists, epidemiologists, and diabetologists. The DPP and its follow-up study are supported by the NIDDK. Ongoing management of DPP resources occurs through the DPP Coordinating Center, and the SHIP study will be complementary to ongoing DPP ancillary studies examining androgens in premenopausal women and androgens in men. The DPP's large, well-characterized, racially/ethnically diverse population and stored plasma provide a unique opportunity to assess the relationships among repeated measures of ESH, adiposity, insulin homeostasis, and glucose intolerance. PUBLIC HEALTH RELEVANCE: Postmenopausal women are at high risk for diabetes, and previous studies suggest that endogenous sex hormones (as opposed to hormone replacement therapy) may play a role. However, previous studies have not examined whether changes in sex hormones are associated with changes in glucose tolerance, and whether such changes might be explained by concurrent changes in adiposity and insulin. Previous studies have not examined the influence of diabetes prevention interventions upon sex hormones. To address these gaps, the proposed SHIP ancillary study will leverage the significant data already collected through the DPP. The SHIP study will provide insight into the pathophysiology of glucose intolerance, and the findings will have implications not only for diabetes prevention but also for other diseases that focus on sex hormones as mediators.